Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that can arise de novo, but much more commonly arises after hormonal therapy for prostate adenocarcinoma (PCA) (PALMGREN et al., Semin Oncol., 34:22-9 (2007)). It is known that the amount of neuroendocrine differentiation increases with disease progression and correlates with patient exposure to long-term androgen deprivation therapy. NEPC reportedly differs histologically from PCA, and is characterized by the presence of small round blue neuroendocrine cells, which do not express androgen receptor (AR) or secrete prostate specific antigen (PSA), but usually express neureondocrine markers such as chromogranin A, synaptophysin, and neuron specific enolase (NSE)(WANG et al., Am J Surg Pathol., 32:65-71 (2008)). The prostate cancer specific TMPRSS2-ERG gene rearrangement (TOMLINS et al., Science, 310:644-8 (2005)) has been reported in approximately 50% of NEPC (LOTAN et al., Mod Pathol. (2011)), similar to the frequency in PCA (MOSQUERA et al., Clin Cancer Res., 15:4706-11 (2009)). This suggests clonal origin of NEPC from PCA and distinguishes NEPC from small carcinomas of other primary sites LOTAN et al., Mod Pathol. (2011), SCHEBLE et al., Mod Pathol., 23:1061-7 (2010), WILLIAMSON et al., Mod Pathol. (2011)). The poor molecular characterization of NEPC accounts in part for the lack of disease specific therapeutics.
The development of treatment related neuroendocrine prostate cancer (t-NEPC, also referred to as anaplastic prostate cancer) is thought to drive approximately 25% of the nearly 34,000 cases/year of lethal prostate cancer in the United States (Jemal et al., CA Cancer J. Clin 61(2): 69-90, 2011). However, because t-NEPC is under-recognized and patients are rarely biopsied to make the diagnosis, this number may actually be higher. Data from autopsy studies suggests that the incidence of t-NEPC may be significantly underestimated (Brawn and Speights, Br J Cancer 59(1):85-88, 1989). With the introduction of new highly potent androgen receptor (AR)-targeted therapies into the clinic, the incidence of t-NEPC will likely escalate. Patients who develop t-NEPC have an aggressive clinical course, often develop visceral or lytic bone metastases, responds only transiently to chemotherapy, and most survive less than one year (PALMGREN et al., Semin Oncol., 34:22-9 (2007)). t-NEPC is becoming an important entity to recognize as all patients eventually develop resistance.